Blanka Klepetářová

Oxidative Catalysis Using the Stoichiometric Oxidant as a Reagent: An Efficient Strategy for Single‐Electron‐Transfer‐Induced Tandem Anion–Radical Reactions

Oxidative single-electron transfer-catalyzed tandem reactions consisting of a conjugate addition and a radical cyclization are reported, which incorporate the mandatory terminal oxidant as a functionality into the product.

General and modular synthesis of isomeric 5-substituted pyridin-2-yl and 6-substituted pyridin-3-yl C-ribonucleosides bearing diverse alkyl, aryl, hetaryl, amino, carbamoyl, and hydroxy groups.

A general modular and practical methodology for preparation of diverse 5-substituted pyridin-2-yl and 6-substituted pyridin-3-yl C-ribonucleosides was developed. Regioselective lithiation of 2,5-dibromopyridine proceeded at position 5 or 2 depending on the solvent, and the resulting bromopyridyl lithium species underwent additions to TBS-protected ribonolactone and follow-up transformations to corresponding acetylated hemiketal intermediates 7 and 10 that were diastereoselectively reduced to give either 5-bromopyridin-2-yl or 6-bromopyridin-3-yl silyl-protected C-ribonucleosides 8 or 11 in 68% and 77% overall yields as pure β-anomers. These bromopyridyl C-nucleoside intermediates were then subjected to a series of palladium-catalyzed cross-coupling reactions, aminations, aminocarbonylations, and hydroxylations to give a series of protected 1β-(5-alkyl-, 5-aryl-, 5-amino-, 5-carbamoyl-, and 5-hydroxypyridin-2-yl)-C-ribonucleosides 13a-i and β-(6-alkyl-, 6-aryl-, 6-amino-, 6-carbamoyl-, and 6-hydroxypyridin-3-yl)-C-ribonucleosides 15a-i. Deprotection of silylated nucleosides by Et(3)N·3HF, TBAF, or TFA gave a series of free C-nucleosides 14a-i and 16a-i.

Synthesis and antiviral activity of N9-[3-fluoro-2-(phosphonomethoxy)propyl] analogues derived from N6-substituted adenines and 2,6-diaminopurines

An efficient method for the synthesis of N(9)-[3-fluoro-2-(phosphonomethoxy)propyl] (FPMP) derivatives of purine bases has been developed. Both (R)- and (S)-enantiomers of the N(6)-substituted FPMP derivatives of adenine and 2,6-diaminopurine were prepared and their anti-human immunodeficiency virus (HIV) and anti-Moloney murine sarcoma virus (MSV) activity was evaluated. Whereas none of the 6-substituted FPMPA derivatives showed any antiviral activity, several FPMPDAP derivatives had a moderate antiretroviral activity. Moreover, the data obtained from the study of the substrate activity of the active derivatives towards N(6)-methyl-AMP aminohydrolase support the notion that the studied N(6)-substituted FPMPDAP derivatives act as prodrugs of the antiretroviral FPMPG analogues.

Search for conglomerate in set of [7]helquat salts: multigram resolution of helicene-viologen hybrid by preferential crystallization.

Investigation of a set of 12 [7]helquat salts by X-ray crystal diffraction led to identification of conglomerate behavior in bis(trifluoroacetate) salt [2][CF(3)CO(2)](2). This is to demonstrate that a systematic search for conglomerates can be performed for a given helicenoid enabling straightforward multigram resolution via preferential crystallization. Subsequently, preferential crystallization of this chiral helicene-viologen hybrid has been established to obtain pure P and M enantiomers on a multigram scale, 5 g each. Furthermore, preparation of nonracemic samples of [7]helquat 2 via diastereomeric (R,R)-dibenzoyltartrate salts is described, and determination of absolute configuration and racemization barrier is also reported.

Azidoperfluoroalkanes: Synthesis and Application in Copper(I)-Catalyzed Azide–Alkyne Cycloaddition

We report an efficient and scalable synthesis of azidotrifluoromethane (CF3 N3 ) and longer perfluorocarbon-chain analogues (RF N3 ; RF =C2 F5 , n C3 F7 , n C8 F17 ), which enables the direct insertion of CF3 and perfluoroalkyl groups into triazole ring systems. The azidoperfluoroalkanes show good reactivity with terminal alkynes in copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), giving access to rare and stable N-perfluoroalkyl triazoles. Azidoperfluoroalkanes are thermally stable and the efficiency of their preparation should be attractive for discovery programs.

Direct C–H amination and C–H chloroamination of 7-deazapurines

Protocols for selective Pd–Cu-catalyzed direct C–H amination or C–H chloroamination of 7-deazapurines with N-chloro-N-alkyl-arylsulfonamides have been developed leading either to 8-(arylsulfonyl)methylamino-7-deazapurines or to 7-chloro-8-(arylsulfonyl)methylamino-7-deazapurines. The scope and limitations of the methods, as well as synthesis of a small series of 6,8,9-tri- and 6,7,8,9-tetrasubstituted 7-deazapurines and deprotection of the sulfonamide are presented.

Synthesis of substituted 6-cyclopropylpurine bases and nucleosides by cross-coupling reactions or cyclopropanations

Synthesis of novel purine bases and nucleosides bearing unsubstituted or substituted cyclopropyl rings in position 6 is reported. Unsubstituted 6-cyclopropylpurines were efficiently prepared by cross-coupling reactions of 6-chloropurines with cyclopropylzinc chloride. 6-Vinylpurines underwent Cu-mediated cyclopropanations with ethyl diazoacetate to give 6-[(ethoxycarbonyl)cyclopropyl]purines that were further transformed to carboxylic acids, amides and alcohols. 6-Cyclopropylpurine ribonucleoside exerted a significant cytostatic effect while all substituted derivatives were inactive.

Highly Functionalized Cyclopentane Derivatives by Tandem Michael Addition/Radical Cyclization/Oxygenation Reactions

Densely functionalized cyclopentane derivatives with up to four consecutive stereocenters are assembled by a tandem Michael addition/single-electron transfer oxidation/radical cyclization/oxygenation strategy mediated by ferrocenium hexafluorophosphate, a recyclable, less toxic single-electron transfer oxidant. Ester enolates were coupled with α-benzylidene and α-alkylidene β-dicarbonyl compounds with switchable diastereoselectivity. This pivotal steering element subsequently controls the diastereoselectivity of the radical cyclization step. The substitution pattern of the radical cyclization acceptor enables a switch of the cyclization mode from a 5-exo pattern for terminally substituted olefin units to a 6-endo mode for internally substituted acceptors. The oxidative anionic/radical strategy also allows efficient termination by oxygenation with the free radical 2,2,6,6-tetramethyl-1-piperidinoxyl, and two C-C bonds and one C-O bond are thus formed in the sequence. A stereochemical model is proposed that accounts for all of the experimental results and allows the prediction of the stereochemical outcome. Further transformations of the synthesized cyclopentanes are reported.

Synthesis of Aliphatic Sulfur Pentafluorides by Oxidation of SF5-Containing Anisole, Phenols, and Anilines

4-(Pentafluorosulfanyl)catechol, 2-amino-4-(pentafluorosulfanyl)phenol, and 2-amino-5-(pentafluorosulfanyl)phenol undergo oxidation by lead tetraacetate at ambient temperature leading to dearomatization and the formation of SF5-substituted nitriles and esters of cis,cis-hexa-2,4-dienedioic (muconic) acid in good yields. 4-(Pentafluorosulfanyl)phenol and 4-(pentafluorosulfanyl)anisole are oxidized by 30% aqueous hydrogen peroxide in concentrated sulfuric acid to provide 2-(5-oxo-3-(pentafluorosulfanyl)-2,5-dihydrofuran-2-yl)acetic acid [3-(pentafluorosulfanyl)muconolactone] and small amounts of side products--SF5-containing maleic and succinic acids. The methods presented are the first examples of the practical synthesis of aliphatic SF5-containing compounds from readily available aromatic ones.

Thiocyanation of closo-Dodecaborate B12H122−. A Novel Synthetic Route and Theoretical Elucidation of the Reaction Mechanism

Although vast experimental experience has been accumulated about the reactions of icosahedral B(12)H(12)(2-) borane cages, little is known about the mechanisms by which these reactions proceed. To address this issue, we have chosen the thiocyanation of B(12)H(12)(2-) and have studied this reaction using both experimental and theoretical methods. First, we present a novel and more convenient synthetic route using in situ generated thiocyanogen, (SCN)(2). The synthesized disubstituted product B(12)H(10)(SCN)(2)(2-) is exclusively the meta positional isomer, as confirmed by the X-ray crystallographic analysis. The quantum chemical calculations at the B3LYP/def2-TZVP//RI-PBE/def2-SVP level show that the free energy differences between the ortho, meta, and para disubstituted species are very small and as such cannot explain the observed positional preferences. The calculations of the kinetic aspects reveal that the reaction is best described as an electrophilic substitution. The calculated isomer preferences for the second SCN substituent are meta > para > ortho. The major outcome of this work is a clear and consistent picture of the electrophilic substitution reaction mechanism of the thiocyanation of B(12)H(12)(2-), thus contributing to our understanding of the general features of boron hydride reactivity.